1. Academic Validation
  2. Rational Design of Novel Anticancer Small-Molecule RNA m6A Demethylase ALKBH5 Inhibitors

Rational Design of Novel Anticancer Small-Molecule RNA m6A Demethylase ALKBH5 Inhibitors

  • ACS Omega. 2021 May 14;6(20):13310-13320. doi: 10.1021/acsomega.1c01289.
Simona Selberg 1 Neinar Seli 2 Esko Kankuri 3 Mati Karelson 1
Affiliations

Affiliations

  • 1 Institute of Chemistry, University of Tartu, Ravila 14a, Tartu 50411, Estonia.
  • 2 Chemestmed, Ltd., Riia tn 130b/2, Tartu 50411, Estonia.
  • 3 Faculty of Medicine, Department of Pharmacology, University of Helsinki, Helsinki 00014, Finland.
Abstract

The RNA 6-N-methyladenosine (m6A) demethylase ALKBH5 has been shown to be oncogenic in several Cancer types, including leukemia and glioblastoma. We present here the target-tailored development and first evaluation of the antiproliferative effects of new ALKBH5 inhibitors. Two compounds, 2-[(1-hydroxy-2-oxo-2-phenylethyl)sulfanyl]acetic acid (3) and 4-{[(furan-2-yl)methyl]amino}-1,2-diazinane-3,6-dione (6), with IC50 values of 0.84 μM and 1.79 μM, respectively, were identified in high-throughput virtual screening of the library of 144 000 preselected compounds and subsequent verification of hits in an m6A antibody-based enzyme-linked immunosorbent assay (ELISA) Enzyme inhibition assay. The effect of these compounds on the proliferation of selected target Cancer cell lines was then measured. In the case of three leukemia cell lines (HL-60, CCRF-CEM, and K562) the cell proliferation was suppressed at low micromolar concentrations of inhibitors, with IC50 ranging from 1.38 to 16.5 μM. However, the effect was low or negligible in the case of another leukemia cell line, Jurkat, and the glioblastoma cell line A-172. These results demonstrate the potential of ALKBH5 inhibition as a cancer-cell-type-selective antiproliferative strategy.

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